Context-Dependent Effects of PARP Inhibitors on Breast Cancer Bone Metastasis

PARP 抑制剂对乳腺癌骨转移的背景依赖性影响

• 批准号: 10551902
• 负责人: WILLIAM Lee KRAUS
• 金额: $ 36.32万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551902
• 关键词: Antibodies; Antineoplastic Agents; Attenuated; BRCA mutations; Binding Proteins; Biochemical; Bone Diseases; Bone Pain; Bone Resorption; Breast Cancer therapy; Cancer Etiology; Cell Death; Cells; ChIP-seq; Chromatin; Clinical; Clinical Trials; Collaborations; Communities; DNA Binding; DNA Repair; Drug resistance; Environment; FDA approved; Family member; Gene Expression Regulation; Genetic; Genetic Transcription; Genetic study; Genomics; Goals; Hypercalcemia; In Vitro; Investigation; Knockout Mice; Life; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Metastatic Neoplasm to the Bone; MicroRNAs; Molecular; Molecular Target; Mus; Mutagenesis; Nature; Neoplasm Metastasis; Osteoclasts; Pathological fracture; Patients; Pharmaceutical Preparations; Pharmacology Study; Play; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Primary Neoplasm; Proliferating; Proteins; Proteomics; Regulation; Resistance; Role; Scheme; Series; Skeleton; TNFSF11 gene; Testing; Therapeutic; Time; advanced breast cancer; analog; bisphosphonate; bone; cancer cell; cancer complication; cancer therapy; candidate identification; cell type; chemical genetics; clinical development; clinically relevant; design; gain of function; genetic approach; in vivo; individualized medicine; inhibitor; inhibitor therapy; innovation; insight; knock-down; loss of function; malignant breast neoplasm; mortality; neoplastic cell; novel; osteoclastogenesis; overexpression; palliative; personalized medicine; pharmacologic; skeletal; spinal cord compression; tool; transcriptome sequencing; tumor; tumor growth

Bone metastasis is a frequent, debilitating and essentially incurable cancer complication. More than 70% of patients with advanced breast cancer have metastatic bone disease, leading to severe bone pain, pathological fracture, life-threatening hypercalcemia, spinal cord compression, limited mobility and increased mortality. During bone metastasis, cancer cells and osteoclasts form a vicious cycle so that cancer cells promote osteoclast differentiation and osteoclasts in turn facilitate cancer cell seeding and proliferation in the skeletal environment. Nonetheless, the current understanding of the intricate mechanisms underlying this malicious cycle is still limited, and the existing osteoclast inhibitor drugs confer no survival benefit. Our overarching goal is to discover new and better treatment for cancer bone metastasis that simultaneously suppresses both cancer cell and osteoclast. In December 2014, an inhibitor of Poly (ADP-ribose) polymerase (PARP), Olaparib, was approved by the FDA for treating elapsed BRCA-defective ovarian cancer. Since then, two more PARP inhibitors have also received FDA approval. Several PARP1/2 dual inhibitors are also currently in clinical trials as breast cancer therapy. Despite these clinical efforts on PARP inhibitors in cancer treatment, little is known about the roles of PARPs in metastasis. Moreover, it is unclear whether and how different PARP family members display distinct functions. In our preliminary studies, we have found that PARP2 loss, but not PARP1 loss, promotes bone metastasis by acting in both osteoclast and tumor cell to enhance osteoclastogenesis; olaparib treatment exacerbates bone metastasis in a manner that is dependent on modifiers such as BRCA status and drug resistance. We hypothesize that PARP2 is a powerful dual suppressor of bone metastasis by regulating key targets in osteoclast and tumor cell to synergistically impede breast cancer malignancy. Here we propose to perform a series of comprehensive analyses to test this hypothesis, combining genetic and pharmacological, gain- and loss-of-function, in vitro and in vivo strategies. In Aim 1, we will determine how PARPs in osteoclast regulate bone metastasis. In Aim 2, we will determine how PARPs in cancer cell regulate bone metastasis. In Aim 3, we will elucidate the molecular and biochemical mechanisms for PARP regulation of bone metastasis by identifying and functionally characterizing key PARP targets. This investigation is highly significant and clinically relevant because it will identify PARP2 as a novel dual suppressor of breast cancer bone metastasis, uncover potential deleterious yet context-dependent effects of current PARP1/2 dual inhibitor cancer drugs to exacerbate skeletal metastasis, reveal important functional distinctions between PARP2 and PARP1, suggest PARP1-specific inhibitors as possibly safer options, highlight the exciting therapeutic potential of PARP2 activation to mitigate breast cancer bone metastasis, and provide crucial insights for personalized medicine and tailored treatment to better design and utilize PARP inhibitors as cancer drugs.

骨转移是一种常见的、使人虚弱的、基本上无法治愈的癌症并发症。超过70%的 晚期乳腺癌患者有转移性骨病，导致严重骨痛、病理改变。 骨折、危及生命的高钙血症、脊髓受压、活动受限和死亡率增加。 在骨转移过程中，癌细胞和破骨细胞形成恶性循环，癌细胞促进 破骨细胞分化和破骨细胞反过来促进癌细胞在骨骼中的种植和增殖 环境。尽管如此，目前对这种恶意行为背后复杂机制的理解 周期仍然有限，现有的破骨细胞抑制剂药物对生存没有好处。我们的首要目标 是发现同时抑制两者的癌症骨转移的新的更好的治疗方法 癌细胞和破骨细胞。2014年12月，多聚(ADP-核糖)聚合酶(PARP)抑制剂奥拉帕利， 被FDA批准用于治疗晚期BRCA缺陷型卵巢癌。从那时起，又有两个PARP 抑制剂也获得了FDA的批准。几种PARP1/2双重抑制剂目前也在进行临床试验 作为乳腺癌的治疗方法。尽管临床上对PARP抑制剂在癌症治疗方面做出了这些努力，但人们对此知之甚少 关于PARPS在肿瘤转移中的作用。此外，目前还不清楚PARP家族是否以及如何不同 成员发挥着不同的功能。在我们的初步研究中，我们发现PARP2丢失，但PARP1没有 丢失，通过作用于破骨细胞和肿瘤细胞来促进破骨细胞的生成，从而促进骨转移； 奥拉帕利治疗以一种依赖于BRCA等修饰剂的方式加剧骨转移 状态和抗药性。我们假设PARP2是一种强大的骨转移双重抑制因子，它通过 调节破骨细胞和肿瘤细胞中的关键靶点以协同抑制乳腺癌的恶性。在这里我们 建议进行一系列全面的分析来检验这一假设，结合遗传和 药理、功能得失、体外和体内策略。在目标1中，我们将确定如何 破骨细胞中的PARPS调控骨转移。在目标2中，我们将确定癌细胞中PARP是如何调节的 骨转移。在目标3中，我们将阐明PARP调节的分子和生化机制。 通过识别和确定关键的PARP靶点来研究骨转移。这项调查是高度 具有重要意义和临床意义，因为它将确定PARP2是一种新的乳腺癌双重抑制因子 骨转移，揭示当前PARP1/2双重抑制剂的潜在有害但上下文相关的影响 癌症药物加剧骨转移，揭示PARP2和PARP2之间重要的功能差异 PARP1，建议PARP1特异性抑制剂可能是更安全的选择，突出了令人兴奋的治疗潜力 PARP2激活以减轻乳腺癌骨转移，并为个性化研究提供关键见解 药物和量身定做的治疗，以更好地设计和利用PARP抑制剂作为癌症药物。